In 1942 Albright and his associates described the features of a new clinical syndrome "pseudohypoparathyroidism" (PHP). Patients with this disorder differ from those with idiopathic hypoparathyroidism: they show characteristic constitutional features (Albright's hereditary osteodystrophy - AHO) and do not respond to exogenous parathyroid hormone. Subsequent to the original report, patients lacking the typical somatic features of AHO but resistant to endogenous and administered PTH have been described. We found previously that in PHP, urinary cyclic AMP does not increase normally in response to PTH administration. This indicated that there is a defective hormone receptor-adenylate cyclase complex in this disorder. We have shown that red cells from patients with PHP + AHO are functionally deficient in a recently isolated protein ("G unit") that serves to couple hormone receptor to the catalytic unit of adenylate cyclase. Our results suggest that reduction in G units is the lesion responsible for hormone resistance in PHP + AHO and imply that the defect is not limited to PTH target organs (kidney and bone). Our recent clinical studies have corroborated this speculation, and redefine PHP with AHO as a disorder of generalized hormone resistance.